title: IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis.
abstract: The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-kappaB signalling and cell survival. The most common mode of regulation by ubiquitin-conjugation involves specialized ubiquitin-binding proteins that bind to ubiquitylated proteins and link them to downstream biochemical processes. Unravelling how the ubiquitin-message is recognized is essential because aberrant ubiquitin-mediated signalling contributes to tumour formation. Recent evidence indicates that inhibitor of apoptosis (IAP) proteins are frequently overexpressed in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival. Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-alpha-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2-MALT1 to activate NF-kappaB. Our data suggest that the UBA domain of cIAP2-MALT1 stimulates NF-kappaB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2-MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2-MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin-binding proteins that contribute to ubiquitin-mediated cell survival, NF-kappaB signalling and oncogenesis.
authors.affiliation: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
authors.forename: Mads
authors.initials: M
authors.lastname: Gyrd-Hansen
authors.forename: Maurice
authors.initials: M
authors.lastname: Darding
authors.forename: Maria
authors.initials: M
authors.lastname: Miasari
authors.forename: Massimo M
authors.initials: MM
authors.lastname: Santoro
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.forename: Tencho
authors.initials: T
authors.lastname: Tenev
authors.forename: Paula C A
authors.initials: PC
authors.lastname: da Fonseca
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Janusz M
authors.initials: JM
authors.lastname: Bujnicki
authors.forename: Scott
authors.initials: S
authors.lastname: Lowe
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010957:Plasmids; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D008156:Luciferases; D005982:Glutathione Transferase